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(Journal of Leukocyte Biology. 2003;73:178-182.)
© 2003 by Society for Leukocyte Biology

Short cytoplasmic SDYMNM segment of CD28 is sufficient to convert CTLA-4 to a positive signaling receptor

Li Yin^*,, Helga Schneider^*,, and Christopher E. Rudd^*,,

^* Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, and Departments of
Medicine and
Pathology, Harvard Medical School, Boston, Massachusetts; and
Department of Haematology, Imperial College of Science, Technology and Medicine, London, United Kingdom

Correspondence: Christopher E. Rudd, Imperial College of Science, Technology and Medicine, Department of Haematolgy, Division of Investigative Science, Faculty of Medicine, Hammersmith Hospital Campus, Du Cane Road, London, W12 ONN, UK. E-mail: c.rudd{at}ic.ac.uk

CD28 and cytotoxic T-lymphocyte antigen (CTLA)-4 are key coreceptors on the surface of T cells that have opposing effects on T cell activation. Although CD28 enhances proliferation, CTLA-4 markedly inhibits the activation process. These opposing roles are particularly surprising given the structural similarity of the cytoplasmic residues of the two receptors. These include the related CD28_SDYMNM and CTLA-4_GVYVKM motifs. In this study, we have directly addressed whether these related motifs may play different roles in the activation process by swapping the CTLA-4_GVYVKM motif with the CD28_SDYMNM motif. Remarkably, stable transfectants of the T cell hybridoma DC27.10 showed that substitution of CTLA-4_GVYVKM was sufficient to convert CTLA-4 from a negative signaling coreceptor to a positive CD28-like coreceptor. CD28_SDYMNM is therefore sufficient to convey positive signals within CTLA-4. These results demonstrate that CD28_SDYMNM and CTLA-4_GVYVKM motifs contain sufficient information to distinguish positive versus negative coreceptor signaling in T cells.

Key Words: coreceptor • phosphatidylinositol 3-kinase

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